ApolipoproteinE (ApoE) is a protein responsible for lipid transport and is implicated in a variety of mechanisms in the central nervous system ranging from neuronal development to brain repair. Unlike murine ApoE, humans have three different isoforms of ApoE: E2, E3, and E4, which differ by single amino acid substitutions. APOE is the strongest genetic risk factor for Alzheimer's Disease (AD), with the E4 allele increasing and E2 allele decreasing one's risk for AD. Although APOE seems to affect processes early in disease development, exactly how APOE affects AD risk is unknown. The objective of this proposal is to test whether APOE genotype affects brain structure and function before AD pathogenesis resulting in E4 carriers being more vulnerable to the damages that occur with aging. If this is true, potential preventative therapeutics for AD could be developed to compensate for the E4 related changes. APOE Targeted Replacement (TR) mice homozygous for E2, E3, or E4 will be used to assess this question. These mice do not develop the overt signs of AD pathogenesis, such as amyloid plaques and tangles, allowing one to separate out any of the confounding changes in brain structure that occur once AD pathology appears. In this mouse model, human APOE alleles are knocked in to replace murine APOE resulting in human APOE expression under the endogenous mouse promoter allowing for its normal regulation. Because the largest overall risk for AD is aging and whether APOE affects aging related brain changes to subsequently alter AD risk is unknown, this proposal will look at two different timepoints in these mice: young (defined as 4-5 months) and old (defined as 1 year). The long term goal is to identify any biochemical markers for future clinical preventative measures in reducing one's susceptibility to AD. Therefore, this proposal will utilize a technique widely used in the clinic: identify the variations in brain structure and function which APOE genotype may modulate as a function of age. Specifically, 1H Magnetic Resonance Spectroscopy, a noninvasive imaging technique that permits the quantification of metabolic biomarkers in vivo, will be applied to obtain information about the dynamic physiological profiles of metabolites in the brain (Aim 1). Furthermore, structural MRI will be used to obtain anatomical information about the brain such as grey matter volume, white matter volume and white matter integrity (Aim 2). If brain atrophy is observed in APOE4 TR mice, this would suggest that E4 carriers may have simplified anatomical connections, which contribute to susceptibility to damages later in life. This proposal will not only contribute to the understanding of AD susceptibility, but also to better understanding the role that APOE plays in normal brain development and aging. Magnetic Resonance Imaging, in order to PUBLIC HEALTH RELEVANCE: ApolipoproteinE, APOE, encodes for a protein involved in cholesterol transport, and is implicated in a variety of mechanisms in the central nervous system ranging from neuronal development to brain repair. APOE is also the strongest genetic risk factor for Alzheimer's Disease and although APOE seems to affect processes early in disease development, exactly how APOE affects Alzheimer's Disease risk is unknown. The goals of this research project are to test whether APOE genotype affects brain structure and function before Alzhiemer's Disease pathogenesis to subsequently alter Alzheimer's Disease risk and whether there are viable biomarkers for these changes, so that Disease could be developed to compensate for APOE related risk. potential preventative therapeutics for Alzheimers